Our overall goal is to understand the physiological consequences of global cerebral hypoxia, and how failure of the normal homeostatic mechanisms progresses to disease. To address this, it is first necessary to define the normal physiological responses to cerebral hypoxia. Cerebral hypoxia is the outcome of many disease processes (pulmonary, cardiac, cerebrovascular), and thus to investigate cerebral homeostasis mechanisms to hypoxia per se, it is important to examine them in isolation from potentially coexistent multi-system disease. In this proposal we use altitude-induced hypoxia (Acute Mountain Sickness - AMS) as a model system of isolated sustained hypoxia to study the normal physiological response mechanisms. This proposal draws hypotheses from traditional high altitude research and from functional MRI studies of cerebral physiology. We will experimentally test these existing models to explain the progression from hypoxic exposure to cerebral disease. Our specific aims are to measure the normal cerebral physiological response to acute (<6 hrs), short-term (2 days) and sustained (7 days) hypoxia (PIO2 = 90 Torr) in healthy individuals, and define the time-dependent physiologic response to hypoxia. Using MRI measurements of cerebral physiology (i.e. changes in CBF, CMRO2, CSF volume &edema) we will experimentally test individual components of the models. To systematically assess the time-course of the normal physiological responses, these measurements will be made over a range of acute and sustained hypoxic exposure. Measurements will be made in the same cohort of human subjects (encompassing AMS-susceptible andAMS-resistant individuals). These studies will provide a comprehensive picture of the cerebral physiological responses to hypoxia, and why some individuals are better able to acclimatize to low oxygen levels-we will establish a basis for understanding why patients with disease respond differently to hypoxia. Designing appropriate clinical interventions to treat chronic cerebral hypoxic decline hinges on such a comprehensive understanding.